CN102417533A - Synthesis method of gemcitabine hydrochloride - Google Patents

Synthesis method of gemcitabine hydrochloride Download PDF

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CN102417533A
CN102417533A CN2011103340196A CN201110334019A CN102417533A CN 102417533 A CN102417533 A CN 102417533A CN 2011103340196 A CN2011103340196 A CN 2011103340196A CN 201110334019 A CN201110334019 A CN 201110334019A CN 102417533 A CN102417533 A CN 102417533A
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顾海成
马玉恒
王伟
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Jiangsu Chia Tai Qingjiang Pharmaceutical Co Ltd
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Abstract

The invention discloses a synthesis method of gemcitabine hydrochloride. The gemcitabine hydrochloride has a molecular formula of C9H11F2N3O4.HCl, the molecular weight of 299.66 and a chemical abstracts service (CAS) registry number of 122111-03-9. The synthesis method of gemcitabine hydrochloride has the advantages of high yield, easiness of preparation of gemcitabine hydrochloride GH-7 having a single configuration, convenience of operation, and relatively stable configuration.

Description

The compound method of gemcitabine hydrochloride
Technical field
The present invention relates to compound method, be specifically related to the compound method of a kind of gemcitabine hydrochloride ((+) 2 ' deoxidation-2,2 ' difluocytosine hydrochloride).
Background technology
Gemcitabine hydrochloride is the cell cycle specific antimetabolitas; Mainly act on the DNA tumour cell of synthesis phase; Be S phase cell,, can stop the progress of G1 phase under certain condition to the S phase; Be the safer effective chemotherapy medication of a up-to-date line of treatment nonsmall-cell lung cancer in late period, can also be used to treat carcinoma of the pancreas.The synthesis technique of this product exists yield low at present, and purifying difficulty height and configuration are prone to problems such as conversion, causes cost high, yields poorly, and is unfavorable for producing in batches, can not meet the need of market.
Summary of the invention
The objective of the invention is to: ((+) 2 ' deoxidation-2 of a kind of gemcitabine hydrochloride is provided; 2 ' the difluocytosine hydrochloride) compound method, adopt this compound method can obtain higher yield, the preparation method of the single configuration of GH-7 is simple; Be convenient to operation, keep the product configuration constant relatively.
Technical solution of the present invention is: this gemcitabine hydrochloride ((+) 2 ' deoxidation-2,2 ' difluocytosine hydrochloride) has following chemical structural formula:
Figure 116020DEST_PATH_IMAGE002
Molecular formula: C 9H 11F 2N 3O 4HCl molecular weight: 299.66 CAS registration number: 122111-03-9.
Wherein, the synthesis step of gemcitabine hydrochloride is:
Figure 2011103340196100002DEST_PATH_IMAGE003
。
Wherein, the concrete synthesis step of gemcitabine hydrochloride is:
The first step: GH-2's is synthetic: with ethane (10L), propane (10L), D-N.F,USP MANNITOL (10KG, 54.9mol), (10g 0.05mol) joins in the reactor anhydrous tindichloride; Be warming up to backflow, reaction solution was clarified after 1 hour, continued reaction 0.5 hour; Cool to 25 ℃, add pyridine (13ml), aceticanhydride (7ml), stirred 10 minutes; Remove solvent under reduced pressure, interior temperature control is below 70 ℃; In debris, add methylene dichloride behind the evaporate to dryness, stirred 30 minutes, placement is spent the night, and obtains GH-2 solution; Second day suction filtration, filtrating suction GH-3 reactor;
Figure 932667DEST_PATH_IMAGE004
；
Second step: the GH-3's is synthetic: with GH-2 (6kg, 22.9mol) solution heat temperature raising to 20 ℃, stir add down sodium periodate (12.5kg, 58.6mol); Slowly drip water, the dropping time is half a hour, and temperature is controlled at 25-30 ℃; Drip off, be controlled at 30～32 ℃ of insulation reaction 2 hours; After reaction finishes, suction filtration, filtrating adds anhydrous sodium sulfate drying and spends the night; Second day suction filtration, the first air distillation of filtrating when the fraction temperature reaches 55 ℃, changes underpressure distillation, collects the fraction of 65-75 ℃/20mmHg, obtains GH-3;
；
The 3rd step: GH-4's is synthetic: (0.5kg 7.7mol) joins in the reactor, and reflux is after 20 minutes with THF/anhydrous diethyl ether (1.4kg/1.13kg), zinc powder; Slowly drip THF/anhydrous diethyl ether (0.94kg; 0.75kg), GH-3 (1kg, 7.7mol), bromine ethyl fluoroacetate (1.4kg, mixing solutions 6.9mol); Rate of addition is advisable to keep refluxing, and the dropping time is 3 hours; Drip off, continue to reflux 1 hour; Reflux to finish postcooling to 0 ℃, stir down and slowly joins in cold mass concentration 5% hydrochloric acid soln, stirred 30 minutes, obtain upper organic phase; Lower floor's water is used ethyl acetate extraction again, merges organic phase, and with saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying spends the night organic phase respectively; Second day suction filtration, filtrate decompression is concentrated into dried, obtains GH-4;
Figure 731995DEST_PATH_IMAGE006
；
The 4th step: GH-5's is synthetic: with acetonitrile (4L), GH-4 (1kg, 3.9mol), Glacial acetic acid min. 99.5 (0.21kg), water (0.4L) drop in the reactor reflux 4 hours; Reflux after the end, begin to drip toluene, the dehydration of air distillation simultaneously; When reaching 92 ℃, interior temperature is dehydration end, concentrating under reduced pressure then; Be concentrated into do after, add ETHYLE ACETATE (1 L) and stir, add activated carbon decolorizing, anhydrous sodium sulfate drying half a hour, solvent evaporated obtains GH-5;
Figure 2011103340196100002DEST_PATH_IMAGE007
；
The 5th step: GH-6's is synthetic: (500g 2.9mol) is added among the 700mlDCM, and stirring at room adds pyridine (7.9g again with compound GH-5; 0.1mol), last slowly dropping THP (336g, 4mol), reaction 10h; Add 500ml water, the separatory extraction, anhydrous sodium sulfate drying obtains GH-6;
Figure 317697DEST_PATH_IMAGE008
；
The 6th step: GH-7's is synthetic: (840g 2.5mol) is added in the anhydrous methanol of 1L, adds catalyst Pt (200mg), and stirring at room feeds hydrogen simultaneously, and the reaction times is 20h, and HPLC detection reaction progress is reacted complete basically with compound GH-6; Filter evaporate to dryness methyl alcohol, obtain the racemization solid phase prod; With the acetic acid ethyl dissolution solid of 200ml, be added dropwise in the sherwood oil of 2L, be cooled to rapidly between subzero 50 to 80 degrees centigrade, recrystallization twice obtains the GH-7 of single S configuration;
Figure 2011103340196100002DEST_PATH_IMAGE009
；
The 7th step: GH-8's is synthetic: (211g 0.625mol) adds among the 600mlDCM, stirs to add triethylamine (94g down with compound GH-7; 0.93mol), drip MsCl (78g, 0.687mol) reaction 3h behind the stirring 10min; Stopped reaction adds the shrend reaction of going out, the DCM extraction; Anhydrous sodium sulfate drying, solvent evaporated obtains GH-8;
Figure 311324DEST_PATH_IMAGE010
；
The 8th step: GH-9's is synthetic: (249g 0.6mol) adds among the 300mlDMF, and (114g 0.6mol), slowly drips cytosine(Cyt) (66.6g, DMF solution 0.6mol) to add tosic acid under the stirring at room with compound GH-8; Stir after 0.5 hour, heating was reacted 4 hours until backflow, and directly evaporate to dryness DMF solvent obtains the salt that tosic acid and product form, i.e. the GH-9 bullion;
Figure 2011103340196100002DEST_PATH_IMAGE011
；
The 9th step: GH-10's is synthetic: compound GH-9 bullion (429g) is added in the salt acid ether of 1000ml, under zero degree, stirs, GH-10 slowly separates out; Stir after 5 hours; Filtration obtains product 150g, through the water acetone recrystallization, obtains the finished product GH-10 again;
Figure 677583DEST_PATH_IMAGE012
。
Advantage of the present invention is:
1 this synthetic route total recovery is higher relatively, generates final product from midbody GH-5, and yield is about 35%, is higher than present patent and bibliographical information.
2 these synthetic routes have realized the acquisition of the single configuration of GH-7, and secondary recrystallization just can make single configuration purity reach specification of quality, and method is simple, are convenient to operation.
3 protection bases have been selected THP unstable under acidic condition, and problems such as deprotection base configuration conversion have been avoided under the alkaline condition in the selection of this blocking group, make retention of configuration constant relatively.
Embodiment
Further specify technical solution of the present invention below in conjunction with embodiment, embodiment can not be interpreted as it is the restriction to technical solution.
Embodiment: according to following steps synthetic hydrochloric acid gemcitabine
The first step: GH-2's is synthetic: with ethane (10L), propane (10L), D-N.F,USP MANNITOL (10KG, 54.9mol), (10g 0.05mol) joins in the reactor anhydrous tindichloride; Be warming up to backflow, reaction solution was clarified after 1 hour, continued reaction 0.5 hour; Cool to 25 ℃, add pyridine (13ml), aceticanhydride (7ml), stirred 10 minutes; Remove solvent under reduced pressure, interior temperature control is below 70 ℃; In debris, add methylene dichloride behind the evaporate to dryness, stirred 30 minutes, placement is spent the night, and obtains GH-2 solution; Second day suction filtration, filtrating suction GH-3 reactor;
；
Second step: the GH-3's is synthetic: with GH-2 (6kg, 22.9mol) solution heat temperature raising to 20 ℃, stir add down sodium periodate (12.5kg, 58.6mol); Slowly drip water, the dropping time is half a hour, and temperature is controlled at 25-30 ℃; Drip off, be controlled at 30～32 ℃ of insulation reaction 2 hours; After reaction finishes, suction filtration, filtrating adds anhydrous sodium sulfate drying and spends the night; Second day suction filtration, the first air distillation of filtrating when the fraction temperature reaches 55 ℃, changes underpressure distillation, collects the fraction of 65-75 ℃/20mmHg, obtains GH-3;
；
The 3rd step: GH-4's is synthetic: (0.5kg 7.7mol) joins in the reactor, and reflux is after 20 minutes with THF/anhydrous diethyl ether (1.4kg/1.13kg), zinc powder; Slowly drip THF/anhydrous diethyl ether (0.94kg; 0.75kg), GH-3 (1kg, 7.7mol), bromine ethyl fluoroacetate (1.4kg, mixing solutions 6.9mol); Rate of addition is advisable to keep refluxing, and the dropping time is 3 hours; Drip off, continue to reflux 1 hour; Reflux to finish postcooling to 0 ℃, stir down and slowly joins in cold mass concentration 5% hydrochloric acid soln, stirred 30 minutes, obtain upper organic phase; Lower floor's water is used ethyl acetate extraction again, merges organic phase, and with saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying spends the night organic phase respectively; Second day suction filtration, filtrate decompression is concentrated into dried, obtains GH-4;
Figure 993661DEST_PATH_IMAGE006
；
The 4th step: GH-5's is synthetic: with acetonitrile (4L), GH-4 (1kg, 3.9mol), Glacial acetic acid min. 99.5 (0.21kg), water (0.4L) drop in the reactor reflux 4 hours; Reflux after the end, begin to drip toluene, the dehydration of air distillation simultaneously; When reaching 92 ℃, interior temperature is dehydration end, concentrating under reduced pressure then; Be concentrated into do after, add ETHYLE ACETATE (1 L) and stir, add activated carbon decolorizing, anhydrous sodium sulfate drying half a hour, solvent evaporated obtain GH-5 (588g, 3.5mol), yield is 89%;
Figure 286364DEST_PATH_IMAGE007
；
The 5th step: GH-6's is synthetic: (500g 2.9mol) is added among the 700mlDCM, and stirring at room adds pyridine (7.9g again with compound GH-5; 0.1mol), last slowly dropping THP (336g, 4mol), reaction 10h; Add 500ml water, separatory extraction, anhydrous sodium sulfate drying; Obtain GH-6 (840g, 2.5mol), yield is 86%;
Figure 427495DEST_PATH_IMAGE008
；
The 6th step: GH-7's is synthetic: (840g 2.5mol) is added in the anhydrous methanol of 1L, adds catalyst Pt (200mg), and stirring at room feeds hydrogen simultaneously, and the reaction times is 20h, and HPLC detection reaction progress is reacted complete basically with compound GH-6; Filter evaporate to dryness methyl alcohol, obtain the racemization solid phase prod; With the acetic acid ethyl dissolution solid of 200ml, be added dropwise in the sherwood oil of 2L, be cooled to rapidly between subzero 50 to 80 degrees centigrade, recrystallization twice, obtain single S configuration GH-7 (211g, 0.625mol), yield is 25%;
Figure 925473DEST_PATH_IMAGE009
；
The 7th step: GH-8's is synthetic: with compound GH-7 (211g 0.625mol) adds among the 600mlDCM, stir add down triethylamine (94g, 0.93mol); Stir and to drip MsCl behind the 10min (stopped reaction adds the shrend reaction of going out for 78g, 0.687mol) reaction 3h; The DCM extraction, anhydrous sodium sulfate drying, solvent evaporated; Obtain GH-8 (249g, 0.6mol), yield is 95%;
Figure 759436DEST_PATH_IMAGE010
；
The 8th step: GH-9's is synthetic: (249g 0.6mol) adds among the 300mlDMF, and (114g 0.6mol), slowly drips cytosine(Cyt) (66.6g, DMF solution 0.6mol) to add tosic acid under the stirring at room with compound GH-8; Stir after 0.5 hour, heating was reacted 4 hours until backflow, and directly evaporate to dryness DMF solvent obtains the salt that tosic acid and product form, i.e. GH-9 bullion 429g;
Figure 710075DEST_PATH_IMAGE011
；
The 9th step: GH-10's is synthetic: compound GH-9 bullion (429g) is added in the salt acid ether of 1000ml, under zero degree, stirs, GH-10 slowly separates out; Stir after 5 hours, filter and obtain product 150g, again through the water acetone recrystallization; Obtain the finished product GH-10 130g, yield is 72%;
Figure 654897DEST_PATH_IMAGE012
。

Claims (3)

1. the compound method of gemcitabine hydrochloride, it is characterized in that: this gemcitabine hydrochloride has following chemical structural formula:
Figure 399547DEST_PATH_IMAGE002
。
2. the compound method of gemcitabine hydrochloride according to claim 1 is characterized in that the step of the compound method of gemcitabine hydrochloride is:
?
Figure 2011103340196100001DEST_PATH_IMAGE003
。
3. the compound method of gemcitabine hydrochloride according to claim 2 is characterized in that the concrete steps of gemcitabine hydrochloride compound method are:
The first step: GH-2's is synthetic: with ethane (10L), propane (10L), D-N.F,USP MANNITOL (10KG, 54.9mol), (10g 0.05mol) joins in the reactor anhydrous tindichloride; Be warming up to backflow, reaction solution was clarified after 1 hour, continued reaction 0.5 hour; Cool to 25 ℃, add pyridine (13ml), aceticanhydride (7ml), stirred 10 minutes; Remove solvent under reduced pressure, interior temperature control is below 70 ℃; In debris, add methylene dichloride behind the evaporate to dryness, stirred 30 minutes, placement is spent the night, and obtains GH-2 solution; Second day suction filtration, filtrating suction GH-3 reactor;
Figure 466729DEST_PATH_IMAGE004
；
Second step: the GH-3's is synthetic: with GH-2 (6kg, 22.9mol) solution heat temperature raising to 20 ℃, stir add down sodium periodate (12.5kg, 58.6mol); Slowly drip water, the dropping time is half a hour, and temperature is controlled at 25-30 ℃; Drip off, be controlled at 30～32 ℃ of insulation reaction 2 hours; After reaction finishes, suction filtration, filtrating adds anhydrous sodium sulfate drying and spends the night; Second day suction filtration, the first air distillation of filtrating when the fraction temperature reaches 55 ℃, changes underpressure distillation, collects the fraction of 65-75 ℃/20mmHg, obtains GH-3;
Figure 2011103340196100001DEST_PATH_IMAGE005
；
The 3rd step: GH-4's is synthetic: (0.5kg 7.7mol) joins in the reactor, and reflux is after 20 minutes with THF/anhydrous diethyl ether (1.4kg/1.13kg), zinc powder; Slowly drip THF/anhydrous diethyl ether (0.94kg; 0.75kg), GH-3 (1kg, 7.7mol), bromine ethyl fluoroacetate (1.4kg, mixing solutions 6.9mol); Rate of addition is advisable to keep refluxing, and the dropping time is 3 hours; Drip off, continue to reflux 1 hour; Reflux to finish postcooling to 0 ℃, stir down and slowly joins in cold mass concentration 5% hydrochloric acid soln, stirred 30 minutes, obtain upper organic phase; Lower floor's water is used ethyl acetate extraction again, merges organic phase, and with saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying spends the night organic phase respectively; Second day suction filtration, filtrate decompression is concentrated into dried, obtains GH-4;
Figure 468446DEST_PATH_IMAGE006
；
The 4th step: GH-5's is synthetic: with acetonitrile (4L), GH-4 (1kg, 3.9mol), Glacial acetic acid min. 99.5 (0.21kg), water (0.4L) drop in the reactor reflux 4 hours; Reflux after the end, begin to drip toluene, the dehydration of air distillation simultaneously; When reaching 92 ℃, interior temperature is dehydration end, concentrating under reduced pressure then; Be concentrated into do after, add ETHYLE ACETATE (1 L) and stir, add activated carbon decolorizing, anhydrous sodium sulfate drying half a hour, solvent evaporated obtains GH-5;
Figure 2011103340196100001DEST_PATH_IMAGE007
；
The 5th step: GH-6's is synthetic: (500g 2.9mol) is added among the 700mlDCM, and stirring at room adds pyridine (7.9g again with compound GH-5; 0.1mol), last slowly dropping THP (336g, 4mol), reaction 10h; Add 500ml water, the separatory extraction, anhydrous sodium sulfate drying obtains GH-6;
Figure 951380DEST_PATH_IMAGE008
；
The 6th step: GH-7's is synthetic: (840g 2.5mol) is added in the anhydrous methanol of 1L, adds catalyst Pt (200mg), and stirring at room feeds hydrogen simultaneously, and the reaction times is 20h, and HPLC detection reaction progress is reacted complete basically with compound GH-6; Filter evaporate to dryness methyl alcohol, obtain the racemization solid phase prod; With the acetic acid ethyl dissolution solid of 200ml, be added dropwise in the sherwood oil of 2L, be cooled to rapidly between subzero 50 to 80 degrees centigrade, recrystallization twice obtains the GH-7 of single S configuration;
?
Figure 2011103340196100001DEST_PATH_IMAGE009
；
The 7th step: GH-8's is synthetic: (211g 0.625mol) adds among the 600mlDCM, stirs to add triethylamine (94g down with compound GH-7; 0.93mol), drip MsCl (78g, 0.687mol) reaction 3h behind the stirring 10min; Stopped reaction adds the shrend reaction of going out, the DCM extraction; Anhydrous sodium sulfate drying, solvent evaporated obtains GH-8;
Figure 548583DEST_PATH_IMAGE010
；
The 8th step: GH-9's is synthetic: (249g 0.6mol) adds among the 300mlDMF, and (114g 0.6mol), slowly drips cytosine(Cyt) (66.6g, DMF solution 0.6mol) to add tosic acid under the stirring at room with compound GH-8; Stir after 0.5 hour, heating was reacted 4 hours until backflow, and directly evaporate to dryness DMF solvent obtains the salt that tosic acid and product form, i.e. the GH-9 bullion;
Figure 2011103340196100001DEST_PATH_IMAGE011
；
The 9th step: GH-10's is synthetic: compound GH-9 bullion (429g) is added in the salt acid ether of 1000ml, under zero degree, stirs, GH-10 slowly separates out; Stir after 5 hours; Filtration obtains product 150g, through the water acetone recrystallization, obtains the finished product GH-10 again;
Figure 225814DEST_PATH_IMAGE012
。
CN2011103340196A 2011-10-28 2011-10-28 Synthesis method of gemcitabine hydrochloride Pending CN102417533A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103864871A (en) * 2014-03-10 2014-06-18 洪军 Gemcitabine hydrochloride compound
CN104262335A (en) * 2014-09-30 2015-01-07 常州市勇毅生物药业有限公司 Preparation method of rivaroxaban
CN105367522A (en) * 2014-08-08 2016-03-02 福建南方制药股份有限公司 Gemcitabine intermediate preparation method
CN106083773A (en) * 2016-05-31 2016-11-09 杭州惠诺医药科技有限公司 3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones
CN107245068A (en) * 2016-07-19 2017-10-13 厦门海乐景生化有限公司 A kind of synthetic method of 1,2,5,6 pairs of isopropylidenes D mannitol
CN107857787A (en) * 2017-10-27 2018-03-30 江苏正大清江制药有限公司 A kind of new method for preparing gemcitabine hydrochloride

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CN101024667A (en) * 2007-03-30 2007-08-29 北京博泰世纪科技发展有限公司 Method for preparing gemcitabine hydrochloride
WO2007117760A2 (en) * 2006-02-06 2007-10-18 Dr. Reddy's Laboratories Ltd. Preparation of gemcitabine
CN101096379A (en) * 2007-05-31 2008-01-02 南京卡文迪许生物工程技术有限公司 Novel highly-solid selectively synthesizing gemcitabine process and intermediate

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* Cited by examiner, † Cited by third party
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US4808614A (en) * 1983-03-10 1989-02-28 Eli Lilly And Company Difluoro antivirals and intermediate therefor
WO2007049295A2 (en) * 2005-10-28 2007-05-03 Arch Pharmalabs Limited An improved one pot process for making key intermediate for gemcitabine hcl
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CN101024667A (en) * 2007-03-30 2007-08-29 北京博泰世纪科技发展有限公司 Method for preparing gemcitabine hydrochloride
CN101096379A (en) * 2007-05-31 2008-01-02 南京卡文迪许生物工程技术有限公司 Novel highly-solid selectively synthesizing gemcitabine process and intermediate

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103864871A (en) * 2014-03-10 2014-06-18 洪军 Gemcitabine hydrochloride compound
CN103864871B (en) * 2014-03-10 2016-03-02 洪军 A kind of gemcitabine hydrochloride compound
CN105367522A (en) * 2014-08-08 2016-03-02 福建南方制药股份有限公司 Gemcitabine intermediate preparation method
CN104262335A (en) * 2014-09-30 2015-01-07 常州市勇毅生物药业有限公司 Preparation method of rivaroxaban
CN106083773A (en) * 2016-05-31 2016-11-09 杭州惠诺医药科技有限公司 3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones
CN106083773B (en) * 2016-05-31 2019-06-14 杭州惠诺医药科技有限公司 The preparation method of the fluoro- 2- methyl-D-ribo-gamma lactone of 3,5- dibenzoyl -2- deoxidation -2-
CN107245068A (en) * 2016-07-19 2017-10-13 厦门海乐景生化有限公司 A kind of synthetic method of 1,2,5,6 pairs of isopropylidenes D mannitol
CN107857787A (en) * 2017-10-27 2018-03-30 江苏正大清江制药有限公司 A kind of new method for preparing gemcitabine hydrochloride

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Application publication date: 20120418